Understanding the Impact of Crohn’s Disease Treatments on the Gut Microbiome

February 06, 2018

Crohn’s disease is an inflammatory bowel disease in which dietary stimuli cause symptomatic flare-ups that manifest as pain, cramping, and diarrhea in patients. These symptoms can not only cause significant physical discomfort, they can also deeply impact functionality and overall quality of life. Unfortunately, conventional treatment options often fail to produce complete and durable relief. As such, there is intense interest from researchers, clinicians, and patients in both a greater understanding of the illness and the development of new treatment protocols.

As a disease of the gastrointestinal tract, the gut microbiome of Crohn’s patients has been the subject of extensive study, and the disease has been found to affect every dimension of the microbiome. The fungal, bacterial, viral, and archaean populations that make up the microbiome are skewed to contain different species and in different proportions in Crohn’s patients in comparison to healthy patients. In fact, the severity of symptoms has been found to correlate to the degree of divergence from the healthy gut microbiome. However, Crohn’s disease itself is not the only variable impacting the makeup of the microbiome; treatments that seek to alleviate Crohn’s symptoms can also disrupt microbiome composition and behavior.

Until recently, the relationship between the microbiome of Crohn’s patients and the impact of treatments on the microbiome was unclear. Now, however, new research is shedding light on the links between treatment and microbiome health, potentially opening up the door to more effective therapies.

Examining the Impact of Crohn’s Treatment on the Microbiome

In 2015, a research cohort led by Dr. James D. Lewis published a study examining how the gut microbiome responds to common therapies for Crohn’s disease and whether dietary interventions could be used to correct for treatment-induced imbalances. The researchers also sought to identify counterproductive treatments for Crohn’s, such as those that offer temporary symptom relief but disrupt the microbiome in a way that ultimately augments symptoms. This study was among the first scientifically rigorous and fully quantitative investigations into the impact of Crohn’s treatment on the microbiome.

In a randomized controlled trial conducted in pediatric Crohn’s patients, the researchers deeply examined the microbiome’s response to treatments by periodically taking stool samples and performing extensive microbiome analysis over the 8-week duration of the trial. Upon analysis, the data confirmed that decreasing intestinal inflammation promotes healthy gut microbiome proportions in Crohn’s patients. However, the researchers also found that some conventional treatment regimens for Crohn’s can disrupt the already compromised microbiome, potentially augmenting existing symptoms or causing the emergence of new symptoms.

Most significantly, the study proved that Crohn’s treatments targeted toward normalizing the microbiomes of patients can provide meaningful clinical benefits. This marks a new approach to Crohn’s treatments, as prior interventions have focused primarily on acute symptoms rather than the possibility of balancing the microbiome for long-term symptoms relief.

To better understand the relationship between the microbiome and Crohn’s treatment, it is valuable to examine each therapy individually.

Antibiotic Therapies

Antibiotic therapies are frequently used as an adjunctive treatment for Crohn’s disease to control flare-ups of inflammation. The rationale for using antibiotics is that an abnormal microbiome’s bacterial blooms damage ileal tissue and causes intense discomfort to patients. However, Dr. Lewis’s study found that antibiotics are counterproductive therapies for Crohn’s due to their impact on the microbiome. While initially effective in reducing symptoms, antibiotic use results in rebound symptoms that causes patients’ GI tracts to relapse into an inflamed state.

The reason for this is that antibiotic therapies destroy most of the bacterial microbiome when administered, removing bacteria-related inflammation in Crohn’s patients. However, while bacteria are cleared away, antibiotics have no impact on the fungal members of the microbiome, which readily multiply in the absence of bacteria. The researchers found that when the pediatric patients who experienced the most severe symptoms were administered antibiotics, fungal populations increased to 175% of their normal size. This fungal expansion causes a different set of symptoms of Crohn’s than those caused by a microbiome populated by bacteria, including more severe bloating and nausea as the result of microbiotal fungi’s proficiency at fermentation. Fungi also cause inflammation and are more likely to cause loose stools than bacterial blooms. This explains why antibiotic therapies for Crohn’s reduce symptoms temporarily, then cause new symptoms that worsen with time.

Steroidal Therapies

Corticosteroids are frequently used in conjunction with antibiotics to combat symptomatic flare-ups of Crohn’s disease because they act as potent immunosuppressors in the ilea, reducing inflammation that may be caused by blooming fungal microbiota. Inflammation disrupts the microbiome by bringing large quantities of leukocytes—like bacteria-destroying phagocytes—to the ileal surfaces. While essential to control bacteria that may be harmful elsewhere in the body, phagocytes in the microbiome end up destroying both beneficial and normal bacteria, causing the proportions of the microbiome to shift. Because they reduce inflammation, steroidal therapies help bring the Crohn’s disease patients closer to normal microbiome proportions.

However, while steroidal therapies can correct some of the drastic changes caused by antibiotic therapies, they cannot address the underlying mechanisms of the microbiome that cause inflammation. Additionally, corticosteroids are not viable for long-term use.

Anti-TNF Therapies

As the newest therapies on the scene, anti-tumor necrosis factor (TNF) therapies are cocktails of antibodies that operate on the GI tract ileal cells’ TNFa receptors, thereby reducing inflammation. By targeting the TNFa receptors, the ileal cells undergo changes that cause a reduction in inflammation. Dr. Lewis’s study found anti-TNF therapies to be the single most effective therapy at reducing inflammation markers, with 62% of the group experiencing reduction of inflammation markers to normal levels.

These results are similar to other studies, including a 2015 study conducted by Drs. Lee and Baldassano, who examined anti-TNF therapies for pediatric Crohn’s disease. They found that pairing anti-TNF therapy with dietary therapy improved quality of life substantially while reducing inflammation markers for 84% of the group within the study cohort. Significantly, they also found that pairing anti-TNF with dietary therapies can restore healthy balance to the gut microbiome: while only about a third of the patients on anti-TNF therapies alone had microbiomes close to the healthy microbiome profile, 84% of patients receiving dietary therapies and anti-TNF therapies had microbiomes that deviated only slightly from the healthy norm. This means using anti-TNF therapies in combination with dietary therapies is among the most promising treatment avenues available for Crohn’s patients.

Dietary Therapies

Dietary therapies have long been the go-to treatment for Crohn’s and have been found to be more effective than steroidal therapies when it comes to healing ileal damage caused by inflammation. While a variety of such diets exist, all are typically constituted with nutrients that minimize the amount of bacterial fermentation performed in the GI tract, which controls bloating and inflammation.

In Dr. Lewis’s study, dietary therapies were analyzed as adjuncts to the other treatments examined by the research cohort. The most significant finding was that dietary therapies can create meaningful symptom relief while also causing the least destructive disturbances and most productive changes in the microbiome of all available therapies. Additionally, dietary therapies affected the microbiome more rapidly than any other form of treatment. Unfortunately, conventional dietary therapies are rarely capable of producing complete remission of symptoms, as baseline levels of inflammation and non-dietary factors can cause flare-ups. As such, further refinement of dietary interventions is necessary to improve durability of remission.

The Future of Crohn’s Treatment

The microbiomes of Crohn’s patients are exceptionally reactive to stimuli and have a much wider range of fluctuation than healthy patients’ microbiomes. As the study by Dr. Lewis’s group demonstrates, some conventional Crohn’s treatments can have a deleterious effect on the already compromised microbiome, reducing treatment efficacy and ultimately aggravating the condition. As such, it is critical for clinicians to consider the impact of treatment on the microbiome when making therapeutic recommendations.

At the same time, the development of therapies designed specifically to restore healthy gut microbiome populations and proportions will be critical to enhancing quality of life for Crohn’s patients. By prioritizing the overall health of the microbiome rather than focusing solely on alleviation of acute symptoms, researchers can usher in a new era of Crohn’s treatments that protect the microbiome and create durable remission of symptoms. Dr. Lewis’s finding that dietary strategies—particularly used in conjunction with anti-TNF therapies—can cultivate a more balanced, resilient microbiome is particularly promising. Identifying dietary formulations and nutritional supplements that optimally maintain the microbiome of Crohn’s patients must thus be a major research goal going forward.